CAG repeat polymorphism within the KCNN3 gene is a significant contributor to susceptibility to anorexia nervosa: a case-control study of female patients and several ethnic groups in the Israeli Jewish population.

The human small-conductance Ca(2+)-activated potassium channel gene KCNN3 has been involved in mechanisms underlying neuronal function and plasticity. A multiallelic CAG repeat polymorphism within the KCNN3 has been associated with schizophrenia and bipolar disorder. We have previously reported in a family-based study that longer CAG repeats are preferentially transmitted to patients with anorexia nervosa (AN). The present study extends the analysis of KCNN3 allele distribution to a larger series of AN female patients and control groups, incorporating information on ethnicity and co-morbidities associated with AN. The data analysis is presented while considering separately the two alleles of each individual, namely a minor (shorter) and a major (longer) allele. This study has found that the KCNN3 allele distribution in the general Israeli population does not differ significantly in at least four Jewish ethnic groups of Ashkenazi, North African, Iraqi, and Yemenite origin. These have been used as control groups in a matched case-control analysis that has demonstrated a significant over-representation of KCNN3 alleles with longer CAG repeats among AN patients (P < 0.001 for the major allele and P = 0.035 for allele sum). Under dichotomization, a significantly higher prevalence of the L allele (>19 repeats) has been observed among AN patients (P < 0.001). While considering AN and co-morbid phenotypes, a tendency towards longer (L) alleles has been observed in the subset of patients with obsessive-compulsive disorder (OCD) co-morbidity. These findings further implicate KCNN3 as a significant contributor to predisposition to AN.     

Neonatal hyperthyrotropinemia: population characteristics,diagnosis, management and outcome after cessation of therapy

Introduction Neonatal hyperthyrotropinaemia (HT), defined by elevated TSH and normal T₄, is either transient or persistent. The eventual outcome of neonatal HT is unpredictable and the management of HT patients is controversial. We assessed perinatal parameters and diagnostic measures that may distinguish between transient and persistent HT, compared with congenital hypothyroidism (CH). We also aimed to recommend optimal treatment in these forms of thyroid impairment. Design and patients A multi‐centre, retrospective study was conducted in six paediatric endocrinology units. Forty‐three HT patients and 83 CH patients were included in the study. Measurements We evaluated differences in birth weight (BW), gestational age (GA), modes of diagnosis, screening and confirmatory T₄ and TSH levels, thyroid imaging results and optimal thyroxine doses between HT and CH and between the two forms of HT. Results Newborns with HT had lower BW and GA than those with CH. Transient (n = 18) and persistent HT (n = 25) patients were indistinguishable by most parameters, but those with persistent HT had a higher prevalence of abnormal thyroid imaging (69%vs 8%; P = 0·005). During treatment, 79% and 55% of transient and persistent HT patients respectively experienced elevated levels of free T_4. Although most HT patients were reevaluated after 2·5 years, six transient HT patients stopped therapy and showed full recovery within the first year of life. Conclusions We recommend obtaining thyroid imaging to distinguish between the two forms of HT. Adherence to recommended doses of thyroxine and probably early cessation of therapy in transient HT can prevent iatrogenic hyperthyroidism in these patients.     

Coronary stent bacterial infection with multiple organ septic emboli

We describe an 80-year-old patient who developed Staphylococcus aureus septicemia several days after the implantation of a double stent in the proximal and mid-left anterior descending artery. The infection was complicated by multiple abscesses in the lungs and liver, as well as by bilateral bacterial endophthalmitis requiring right vitrectomy. Long-term antibiotic treatment was successful. Rarity notwithstanding, heightened awareness of this potential complication of a common cardiac procedure is important since diagnosis and immediate therapy are mandatory.     

A familial thyrotropin (TSH) receptor mutation provides in vivo evidence that the inositol phosphates/Ca2+ cascade mediates TSH action on thyroid hormone synthesis

CONTEXT: In the human thyroid gland, TSH activates both the cAMP and inositol phosphates (IP) signaling cascades via binding to the TSH receptor (TSHR). Biallelic TSHR loss-of-function mutations cause resistance to TSH, clinically characterized by hyperthyrotropinemia, and normal or reduced thyroid gland volume, thyroid hormone output, and iodine uptake. OBJECTIVE: We report and study a novel familial TSHR mutation (L653V). RESULTS: Homozygous individuals expressing L653V had euthyroid hyperthyrotropinemia. Paradoxically, patients had significantly higher 2-h radioiodide uptake and 2- to 24-h radioiodide uptake ratios compared with heterozygous, unaffected family members, suggesting an imbalance between iodide trapping and organification. In transfected COS-7 cells, the mutant TSHR had normal surface expression, basal activity, and TSH-binding affinity, equally (2.2-fold) increased EC50 values for TSH-induced cAMP and IP accumulation, and normal maximum cAMP generation. In contrast, the efficacy of TSH for generating IP was more than 7-fold lower with the mutant compared with wild-type TSHR. CONCLUSIONS: We identified and characterized a TSHR defect, preferentially affecting the IP pathway, with a phenotype distinct from previously reported loss-of-function mutations. Results provide the first in vivo evidence for the physiological role of the TSHR/IP/Ca2+ cascade in regulating iodination. According to systematic in vitro mutagenesis studies, other TSHR mutations can result in even complete loss of IP signaling with retained cAMP induction. We hypothesize that such TSHR mutations could be the cause in unexplained partial organification defects.     

Novel mutations in epithelial sodium channel (ENaC) subunit genes and phenotypic expression of multisystem pseudohypoaldosteronism

OBJECTIVES: Multisystem pseudohypoaldosteronism (PHA) is a rare autosomal recessive aldosterone unresponsiveness syndrome that results from mutations in the genes encoding epithelial sodium channel (ENaC) subunits alpha, beta and gamma. In this study we examined three PHA patients to identify mutations responsible for PHA with different clinical presentations. PATIENTS: All three patients presented uniformly with symptoms of severe salt-loss during the first week of life and were hospitalized for up to a year. Beyond infancy, one of the patients showed mild renal salt loss and had no lower respiratory tract infections until 8 years of age, while the other patients continue with a severe course. RESULTS: We sequenced the complete coding regions and intron-exon junctions of the genes encoding alpha, beta and gamma subunits of ENaC for all patients. The results revealed that the mild case represents a novel compound heterozygote including a missense (Gly327Cys) mutation in the alphaENaC gene. Sequences of relatives over three generations confirmed that the missense mutation co-segregates with PHA. This mutation was not found in 60 control subjects. The other patients with severe PHA had two homozygous mutations, a novel deletion mutation in exon 8 of the alphaENaC gene and a splice site mutation in intron 12 of the betaENaC gene. Most of the PHA-causing mutations appear in the alphaENaC gene located on chromosome 12 rather than in the beta and gammaENaC genes located tandemly on chromosome 16. However, the frequency of sequence variants in patients and control subjects showed no difference between genes. CONCLUSIONS: Severe PHA cases are associated with mutations leading to absence of normal-length alpha, beta or gammaENaC, while a mild case has been found to be associated with a missense mutation in alphaENaC. The predominance of PHA-causing mutations in the alphaENaC gene may be related to the function of this subunit.